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Aim: We want to verify the correlation between the increasing use of novel nicotine-containing products (NNCPs) and non-nicotine delivery products (NNDPs) among young individuals and the escalating negative health consequences, necessitating their prohibition., Methods: We performed a comprehensive analysis of the most relevant literature about the utilisation of NNCPs and NNDPs among young individuals and their health effects., Results: Despite being initially seen as less harmful alternatives, for smokers aiming to quit, these products have become more popular due to misleading marketing claims. Teenagers using NNCPs and NNDPs, despite having no smoking history, are more likely to transition to tobacco smoking. Consistent use can lead to health issues like pulmonary damage, asthma, and cardiovascular and ocular problems., Conclusion: The EAP and the ECPCP endorse the WHO's appeal to outlaw these hazardous products. They urge European governments to forbid the sale of NNCPs and NNDPs to children and adolescents in order to safeguard their well-being. They also propose specific recommendations (box 4) to support this cause., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Social inequalities in child mental health are an important public health concern. Whilst previous studies have examined inequalities at a single time point, very few have used repeated measures outcome data to describe how these inequalities emerge. Our aims were to describe social inequalities in child internalising and externalising problems across multiple countries and to explore how these inequalities change as children age., Methods: We used longitudinal data from eight birth cohorts containing participants from twelve countries (Australia, Belgium, Denmark, France, Germany, Greece, Italy, Netherlands, Poland, Norway, Spain and the United Kingdom). The number of included children in each cohort ranged from N = 584 (Greece) to N = 73,042 (Norway), with a total sample of N = 149,604. Child socio-economic circumstances (SEC) were measured using self-reported maternal education at birth. Child mental health outcomes were internalising and externalising problems measured using either the Strengths and Difficulties Questionnaire or the Child Behavior Checklist. The number of data collection waves in each cohort ranged from two to seven, with the mean child age ranging from two to eighteen years old. We modelled the slope index of inequality (SII) using sex-stratified multi-level models., Results: For almost all cohorts, at the earliest age of measurement children born into more deprived SECs had higher internalising and externalising scores than children born to less deprived SECs. For example, in Norway at age 2 years, boys born to mothers of lower education had an estimated 0.3 (95% CI 0.3, 0.4) standard deviation higher levels of internalising problems (SII) compared to children born to mothers with high education. The exceptions were for boys in Australia (age 2) and both sexes in Greece (age 6), where we observed minimal social inequalities. In UK, Denmark and Netherlands inequalities decreased as children aged, however for other countries (France, Norway, Australia and Crete) inequalities were heterogeneous depending on child sex and outcome. For all countries except France inequalities remained at the oldest point of measurement., Conclusions: Social inequalities in internalising and externalising problems were evident across a range of EU countries, with inequalities emerging early and generally persisting throughout childhood., (© 2024. The Author(s).)

Breastfeeding practices require improvement. We performed a systematic review of randomised controlled trials (RCTs) and analytic observational studies to assess effects of mobile applications (apps) aiming to support and promote breastfeeding targeting pregnant women, mothers of infants or their partners, on breastfeeding outcomes. We searched MEDLINE, EMBASE, Cochrane CENTRAL and Association of Computing Machinery Digital Library from 1 July 2008 to 29 November 2022, with lack of coverage of the most recent period before publication date being a limitation of this review. We performed meta-analyses of findings from RCTs on primary outcomes, namely early breastfeeding initiation, exclusive and any breastfeeding rates. Joanna Briggs Institute tools were used for risk of bias assessment. Six RCTs, one quasi-experimental and two cohort studies, mainly from high-income countries, were included. Most studies focused on maternal app usage starting from pregnancy. One study targeted fathers as app-users. Population characteristics, such as parity or delivery mode, apps scope of content and applied active components varied between studies. Main methodological limitations of studies were baseline differences between groups and lack of blinding. Compared to controls, app usage tended to increase the odds of exclusive breastfeeding. This nonsignificant effect was most pronounced at 1-1.5 months (n = 1294, odds ratio 1.45 (95% Confidence Interval, CI 0.83, 2.54), with considerable heterogeneity between studies [I 2 77%]), but less so at 3 and 6 months post-partum. The odds of early breastfeeding initiation, any breastfeeding at all time points were similar among groups. However, two cohort studies reported increased odds of exclusive and/or any breastfeeding at different time points. In conclusion, evidence is insufficient to show sustained beneficial effects of breastfeeding promotion and support through mobile apps on breastfeeding rates., (© 2024 The Author(s). Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Introduction: The Medical Device Regulation (EU)745/2017, increased the regulatory requirements and thus the time and the cost associated with marketing medical devices. For a majority of medical device manufacturers, this has lead to reconsiderations of their product portfolio. The risk of important or essential devices being withdrawn is particularly relevant for pediatric patients and other rare disease patients where limited numbers of devices can be sold and hence the investment needed may not be recovered. This generates critical challenges and opportunities from a regulatory and public health perspective., Areas Covered: This paper is based upon the experience of the authors who contributed to working groups, guidance development and research related to orphan and pediatric devices. We examine the use of medical devices in orphan and pediatric conditions, the relevant aspects of regulations and associated guidance, and we suggest possible policy and practice interventions to ensure the continued availability of essential devices for children and people with rare diseases., Expert Opinion: We recommend a more proactive approach to identifying devices at risk and essential devices, increasing the use of exceptional market approvals, expanding the role of expert panels, engaging with the rare disease communities and supporting registries and standards.

Context: Milk protein contains high concentrations of branched-chain amino acids (BCAA) that play a critical role in anabolism and are implicated in the onset of obesity and chronic disease. Characterizing BCAA catabolism in the postprandial phase could elucidate the impact of protein intake on obesity risk established in the "early protein hypothesis.", Objective: To examine the acute effects of protein content of young child formulas as test meals on BCAA catabolism, observing postprandial plasma concentrations of BCAA in relation to their degradation products., Methods: The TOMI Add-On Study is a randomized, double-blind crossover study in which 27 healthy adults consumed 2 isocaloric young child formulas with alternating higher (HP) and lower (LP) protein and fat content as test meals during separate interventions, while 9 blood samples were obtained over 5 hours. BCAA, branched-chain α-keto acids (BCKA), and acylcarnitines were analyzed using a fully targeted HPLC-ESI-MS/MS approach., Results: Mean concentrations of BCAA, BCKA, and acylcarnitines were significantly higher after HP than LP over the 5 postprandial hours, except for the BCKA α-ketoisovalerate (KIVA). The latter metabolite showed higher postprandial concentrations after LP. With increasing mean concentrations of BCAA, concentrations of corresponding BCKA, acylcarnitines, and urea increased until a breakpoint was reached, after which concentrations of degradation products decreased (for all metabolites except valine and KIVA and Carn C4:0-iso)., Conclusion: BCAA catabolism is markedly influenced by protein content of the test meal. We present novel evidence for the apparent saturation of the BCAA degradation pathway in the acute postprandial phase up to 5 hours after consumption., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background and Aims: Endothelial dysfunction (ED) is considered to be a major driver of the increased incidence of cardiovascular disease in primary aldosteronism (PA). The functionality of the epoxyeicosatrienoic acid (EET) pathway, involving the release of beneficial endothelium-derived lipid mediators, in PA is unknown. Evidence suggests this pathway to be disturbed in various models of experimental hypertension. We therefore assessed EET production in primary human coronary artery endothelial cells exposed to aldosterone excess and measured circulating EET in patients with PA., Methods: We used qPCR to investigate changes in the expression levels of essential genes for the synthesis and degradation of EET, calcium imaging to address the functional impact on overall endothelial function, as well as mass spectrometry to determine endothelial synthetic capacity to release EET upon stimulation. RNA-seq was performed to gain further mechanistic insights. Eicosanoid concentrations in patient's plasma were also determined by mass spectrometry., Results: Aldosterone, while eliciting proinflammatory VCAM1 expression and disturbed calcium response to acetylcholine, did not negatively affect stimulated release of endothelial EET. Likewise, no differences were observed in eicosanoid concentrations in plasma from patients with PA when compared to essential hypertensive controls. However, an inhibitor of soluble epoxide hydrolase abrogated aldosterone-mediated VCAM1 induction and led to a normalized endothelial calcium response probably by restoring expression of CHRNE., Conclusion: EET release appears intact despite aldosterone excess. Epoxide hydrolase inhibition may revert aldosterone-induced functional changes in endothelial cells. These findings indicate a potential new therapeutic principle to address ED, which should be explored in future preclinical and clinical trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Childhood obesity increases metabolic disease risk. Underlying mechanisms remain unknown. We examined associations of body mass index (BMI), total body fat mass, and visceral fat mass with serum metabolites at school-age, and explored whether identified metabolites improved the identification of children at risk of a metabolically unhealthy phenotype., Methods: We performed a cross-sectional analysis among 497 children with a mean age of 9.8 (95% range 9.1, 10.6) years, participating in a population-based cohort study. We measured BMI, total body fat mass using DXA, and visceral fat mass using MRI. Serum concentrations of amino-acids, non-esterified-fatty-acids, phospholipids, and carnitines were determined using LC-MS/MS. Children were categorized as metabolically healthy or metabolically unhealthy, according to BMI, blood pressure, lipids, glucose, and insulin levels., Results: Higher BMI and total body fat mass were associated with altered concentrations of branched-chain amino-acids, essential amino-acids, and free carnitines. Higher BMI was also associated with higher concentrations of aromatic amino-acids and alkyl-lysophosphatidylcholines (FDR-corrected p-values < 0.05). The strongest associations were present for Lyso.PC.a.C14.0 and SM.a.C32.2 (FDR-corrected p-values < 0.01). Higher visceral fat mass was only associated with higher concentrations of 6 individual metabolites, particularly Lyso.PC.a.C14.0, PC.aa.C32.1, and SM.a.C32.2. We selected 15 metabolites that improved the prediction of a metabolically unhealthy phenotype, compared to BMI only (AUC: BMI: 0.59 [95% CI 0.47,0.71], BMI + Metabolites: 0.91 [95% CI 0.85,0.97])., Conclusions: An adverse childhood body fat profile, characterized by higher BMI and total body fat mass, is associated with metabolic alterations, particularly in amino acids, phospholipids, and carnitines. Fewer associations were present for visceral fat mass. We identified a metabolite profile that improved the identification of impaired cardiometabolic health in children, compared to BMI only., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Higher early-life animal protein intake is associated with a higher childhood obesity risk compared to plant protein intake. Differential DNA methylation may represent an underlying mechanism., Methods: We analysed associations of infant animal and plant protein intakes with DNA methylation in early (2-6 years, N  = 579) and late (7̄-12 years, N  = 604) childhood in two studies. Study-specific robust linear regression models adjusted for relevant confounders were run, and then meta-analysed using a fixed-effects model. We also performed sex-stratified meta-analyses. Follow-up analyses included pathway analysis and eQTM look-up., Results: Infant animal protein intake was not associated with DNA methylation in early childhood, but was associated with late-childhood DNA methylation at cg21300373 ( P  = 4.27 × 10¯ 8 , MARCHF1 ) and cg10633363 ( P  = 1.09 × 10¯ 7 , HOXB9 ) after FDR correction. Infant plant protein intake was associated with early-childhood DNA methylation at cg25973293 ( P  = 2.26 × 10 -7 , C1orf159 ) and cg15407373 ( P  = 2.13 × 10 -7 , MBP ) after FDR correction. There was no overlap between the findings from the animal and plant protein analyses. We did not find enriched functional pathways at either time point using CpGs associated with animal and plant protein. These CpGs were not previously associated with childhood gene expression. Sex-stratified meta-analyses showed sex-specific DNA methylation associations for both animal and plant protein intake., Conclusion: Infant animal protein intake was associated with DNA methylation at two CpGs in late childhood. Infant plant protein intake was associated with DNA methylation in early childhood at two CpGs. A potential mediating role of DNA methylation at these CpGs between infant protein intake and health outcomes requires further investigation.

Weight faltering (WF) has been associated with stunting and with long-term adverse consequences for health and development. Nutritional care for managing WF may consist of giving nutritional advice (NA) and/or provision of oral nutrition supplements (ONSs). In this study, we aimed to evaluate practical management options in the community for infants with WF aged 6-12 months. This nonrandomized clinical trial was conducted in the community of Makassar, South Sulawesi, from March 2022 to March 2023. A total of 1013 infants were enrolled for screening. Anthropometric measures were performed in 913 infants, of which 170 showed WF below the 15th percentile of the WHO weight increment table without stunting. Infants with a weight increment below P5th were assigned to receive NA plus ONS, while infants between P5th and below P15th were assigned to receive only NA. At the second and third months, ONSs were administered to WF infants who were below P15th. One month after the intervention, 87/105 infants in the NA-plus-ONS group (82.8%) and 52/65 infants in the NA-only group (80%) were no longer WF. After 3 months, infants in the NA-plus-ONS group achieved greater weight gain than infants in the NA group (264.1 g vs. 137.4 g, p < 0.001) as well as greater length gain (2.35 cm vs. 2.14 cm, p < 0.001). WF management should be started at below P15th to achieve a better result. Infants with greater nutritional deficits should be assigned to receive the combination of NA plus ONSs to achieve a higher rate of resolution of growth.

Aim: The aim of this study was to assess how aware European paediatricians were of the risks faced by children who swallowed button batteries and the advice for managing such cases., Methods: An Internet-based survey was conducted among European paediatricians between 1 April 2023 and 31 May 2023. The researchers contacted members of the European Academy of Paediatrics Research in Ambulatory Setting Network and a number of European national paediatric societies., Results: Responses were received from 605 paediatricians (66.0% females) in 41 countries and 64.5% had encountered cases of button battery ingestion. Only 31.2% had received specific training and only 35.7% were familiar with the advice issued by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the European Academy of Pediatrics. While 90.8% of respondents correctly recognised the need for hospitalisation of a child after button battery ingestion, only 30.1% of them identified all symptoms and 58.2% could accurately determine the appropriate diagnostic scope. One in ten underestimated the health or life risks. These deficiencies were significantly attributed to a lack of adequate training (p < 0.01). The overwhelming majority of the respondents expressed the need to increase awareness among physicians and childcare providers, mainly through social media campaigns and advertisements., Conclusion: European paediatricians were insufficiently aware of button battery ingestion risks and management, with significant gaps in training and familiarity with advice. Respective education for medical practitioners and raising public awareness should be markedly strengthened., (© 2024 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: To investigate the associations of physical activity (PA) and sedentary behaviour in early childhood with asthma and reduced lung function in later childhood within a large collaborative study., Design: Pooling of longitudinal data from collaborating birth cohorts using meta-analysis of separate cohort-specific estimates and analysis of individual participant data of all cohorts combined., Setting: Children aged 0-18 years from 26 European birth cohorts., Participants: 136 071 individual children from 26 cohorts, with information on PA and/or sedentary behaviour in early childhood and asthma assessment in later childhood., Main Outcome Measure: Questionnaire-based current asthma and lung function measured by spirometry (forced expiratory volume in 1 s (FEV 1 ), FEV 1 /forced vital capacity) at age 6-18 years., Results: Questionnaire-based and accelerometry-based PA and sedentary behaviour at age 3-5 years was not associated with asthma at age 6-18 years (PA in hours/day adjusted OR 1.01, 95% CI 0.98 to 1.04; sedentary behaviour in hours/day adjusted OR 1.03, 95% CI 0.99 to 1.07). PA was not associated with lung function at any age. Analyses of sedentary behaviour and lung function showed inconsistent results., Conclusions: Reduced PA and increased sedentary behaviour before 6 years of age were not associated with the presence of asthma later in childhood., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Food Parenting Practices (FPPs) include the practices parents use in the act of feeding their children, which may further influence their health., Objectives: To assess associations between changes in FPPs (permissiveness, food availability, guided choices, water encouragement, rules and limits and the use of food as reward) over 1 year and dietary intake (water, energy-dense/nutrient-poor and nutrient-dense foods) at follow-up in 4- to 6-year-old preschool-aged children., Methods: Longitudinal data from the control group of the ToyBox study, a cluster-randomized controlled intervention study, was used (NCT02116296). Multilevel ordinal logistic regression analyses including FPP as the independent variables and dietary intake as outcome., Results: Nine hundred sixty-four parent-child dyads (50.5% boys and 95.0% mothers) were included. Limited changes on the use of FPPs were observed over time. Nevertheless, in boys, often having F&V at home was associated with higher F&V consumption (OR = 6.92 [1.58; 30.38]), and increasing home availability of F&V was directly associated with higher water consumption (OR = 7.62 [1.63; 35.62]). Also, not having sweets or salty snacks available at home was associated with lower consumption of desserts (OR = 4.34 [1.75; 10.75]). In girls, having F&V availability was associated with higher F&V consumption (OR = 6.72 [1.52; 29.70]) and lower salty snack consumption (OR = 3.26 [1.50; 7.10]) and never having soft drinks at home was associated with lower consumption of sweets (OR = 7.89 [6.32; 9.86]). Also, never being permissive about soft drink consumption was associated with lower soft drink consumption (OR = 4.09 [2.44; 6.85])., Conclusion: Using favorable FPPs and avoiding the negative ones is prospectively associated with healthier dietary intake, especially of F&V, and less intake of soft drinks, desserts, and salty snacks., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paloma Flores-Barrantes reports financial support was provided by Government of Aragon Department of Education Culture and Sports. Pilar De Miguel-Etayo reports financial support was provided by Carlos III Health Institute., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To explore occupational and non-occupational risk and protective factors for the coronavirus disease 2019 (COVID-19) in healthcare workers (HCWs)., Methods: Serum specimens and questionnaire data were obtained between October 7 and December 16, 2021 from COVID-19-vaccinated HCWs at a quaternary care hospital in Munich, Germany, and were analyzed in the RisCoin Study., Results: Of 3,696 participants evaluated, 6.6% have had COVID-19 at least once. Multivariate logistic regression analysis identified working in patient care occupations (7.3% had COVID-19, 95% CI 6.4-8.3, P r  = 0.0002), especially as nurses, to be a potential occupation-related COVID-19 risk factor. Non-occupational factors significantly associated with high rates of the disease were contacts to COVID-19 cases in the community (12.8% had COVID-19, 95% CI 10.3-15.8, P r  < 0.0001), being obese (9.9% had COVID-19, 95% CI 7.1-13.5, P r  = 0.0014), and frequent traveling abroad (9.4% had COVID-19, 95% CI 7.1-12.3, P r  = 0.0088). On the contrary, receiving the basic COVID-19 immunization early during the pandemic (5.9% had COVID-19, 95% CI 5.1-6.8, P r  < 0.0001), regular smoking (3.6% had COVID-19, 95% CI 2.1-6.0, P r  = 0.0088), living with the elderly (3.0% had COVID-19, 95% CI 1.0-8.0, P r  = 0.0475), and frequent consumption of ready-to-eat meals (2.6% had COVID-19, 95% CI 1.1-5.4, P r  = 0.0045) were non-occupational factors potentially protecting study participants against COVID-19., Conclusion: The newly discovered associations between the living situation, traveling as well as dietary habits and altered COVID-19 risk can potentially help refine containment measures and, furthermore, contribute to new mechanistic insights that may aid the protection of risk groups and vulnerable individuals., (© 2024. The Author(s).)

Objective: To conduct a systematic review and meta-analysis of case-control and cohort human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on esophageal cancer (EC), cancer of the gastroesophageal junction (GEJ), and gastric cancer (GC) in blood and tissue., Background: Upper gastrointestinal cancers (UGC), predominantly EC, GEJ, and GC, are malignant tumour types with high morbidity and mortality rates. Numerous studies have focused on metabolomic profiling of UGC in recent years. In this systematic review and meta-analysis, we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with EC, GEJ and GC., Methods: Following the PRISMA procedure, a systematic search of four databases (Embase, PubMed, MEDLINE, and Web of Science) for molecular epidemiologic studies on the metabolomic profiles of EC, GEJ and GC was conducted and registered at PROSPERO (CRD42023486631). The Newcastle-Ottawa Scale (NOS) was used to benchmark the risk of bias for case-controlled and cohort studies. QUADOMICS, an adaptation of the QUADAS-2 (Quality Assessment of Diagnostic Accuracy) tool, was used to rate diagnostic accuracy studies. Original articles comparing metabolite patterns between patients with and without UGC were included. Two investigators independently completed title and abstract screening, data extraction, and quality evaluation. Meta-analysis was conducted whenever possible. We used a random effects model to investigate the association between metabolite levels and UGC., Results: A total of 66 original studies involving 7267 patients that met the required criteria were included for review. 169 metabolites were differentially distributed in patients with UGC compared to healthy patients among 44 GC, 9 GEJ, and 25 EC studies including metabolites involved in glycolysis, anaerobic respiration, tricarboxylic acid cycle, and lipid metabolism. Phosphatidylcholines, eicosanoids, and adenosine triphosphate were among the most frequently reported lipids and metabolites of cellular respiration, while BCAA, lysine, and asparagine were among the most commonly reported amino acids. Previously identified lipid metabolites included saturated and unsaturated free fatty acids and ketones. However, the key findings across studies have been inconsistent, possibly due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group., Conclusion: Thus far, metabolomic studies have provided new opportunities for screening, etiological factors, and biomarkers for UGC, supporting the potential of applying metabolomic profiling in early cancer diagnosis. According to the results of our meta-analysis especially BCAA and TMAO as well as certain phosphatidylcholines should be implicated into the diagnostic procedure of patients with UGC. We envision that metabolomics will significantly enhance our understanding of the carcinogenesis and progression process of UGC and may eventually facilitate precise oncological and patient-tailored management of UGC., (© 2024. The Author(s).)

Healthcare professionals (HCPs) have vital roles in providing evidence-based care to promote healthy micronutrient nutrition in early life. Providing such care requires scalable training to strengthen knowledge and confident application of effective behaviour change skills. Among 33 public and private HCPs (primarily dietitians) in South Africa, we evaluated the behaviour change aspects of a technology-enabled National Qualification Sub-Framework level 6 programme, Improving Early Nutrition and Health in South Africa ('ImpENSA'). This programme comprises two self-directed micronutrient and behaviour change knowledge-based eLearning and one facilitated online practical skills modules to improve maternal and infant micronutrient nutrition. Using assessments, questionnaires and interviews, we collected data at baseline, after module completion and at 3-month follow-up after programme completion. Questionnaire and interview data showed major improvements in understanding of and attitudes towards person-centred behaviour change support immediately following the eLearning module on behaviour change. The assessment pass rate increased from 38% at baseline to 88% postmodule, demonstrating significant knowledge gain in behaviour change support. Intention to change practice towards a person-centred approach was high and many had already started implementing changes. Three months postprogramme, support was centred around patients' needs. Open relationships with patients, improved patient outcomes and increased job satisfaction were among reported outcomes. Many reported becoming better change facilitators and reflective practitioners. Additional improvements in understanding and attitudes to behaviour change support were evident, reinforced by making changes and experiencing positive outcomes. The findings suggest that technology-enabled learning can equip HCPs with knowledge and skills to effectively support behaviour change for healthy micronutrient nutrition during pregnancy and infancy., (© 2024 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Background: Infant formulas are typically manufactured using skimmed milk, whey proteins, and vegetable oils, which excludes milk fat globule membranes (MFGM). MFGM contains polar lipids, including sphingomyelin (SM)., Objective: The objective of this study was comparison of infant plasma SM and acylcarnitine species between infants who are breastfed or receiving infant formulas with different fat sources., Methods: In this explorative study, we focused on SM and acylcarnitine species concentrations measured in plasma samples from the TIGGA study (ACTRN12608000047392), where infants were randomly assigned to receive either a cow milk-based infant formula (CIF) with vegetable oils only or a goat milk-based infant formula (GIF) with a goat milk fat (including MFGM) and vegetable oil mixture to the age ≥4 mo. Breastfed infants were followed as a reference group. Using tandem mass spectrometry, SM species in the study formulas and SM and acylcarnitine species in plasma samples collected at the age of 4 mo were analyzed., Results: Total SM concentrations (∼42 μmol/L) and patterns of SM species were similar in both formulas. The total plasma SM concentrations were not different between the formula groups but were 15 % (CIF) and 21% (GIF) lower in the formula groups than in the breastfed group. Between the formula groups, differences in SM species were statistically significant but small. Total carnitine and major (acyl) carnitine species were not different between the groups., Conclusions: The higher total SM concentration in breastfed than in formula-fed infants might be related to a higher SM content in human milk, differences in cholesterol metabolism, dietary fatty acid intake, or other factors not yet identified. SM and acylcarnitine species composition in plasma is not closely related to the formula fatty acid composition. This trial was registered at Australian New Zealand Clinical Trials Registry as ACTRN12608000047392., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

International sharing of cohort data for research is important and challenging. We explored the feasibility of multicohort federated analyses by examining associations between 3 pregnancy exposures (maternal education, exposure to green vegetation, and gestational diabetes) and offspring body mass index (BMI) from infancy to age 17 years. We used data from 18 cohorts (n = 206,180 mother-child pairs) from the EU Child Cohort Network and derived BMI at ages 0-1, 2-3, 4-7, 8-13, and 14-17 years. Associations were estimated using linear regression via 1-stage individual participant data meta-analysis using DataSHIELD. Associations between lower maternal education and higher child BMI emerged from age 4 and increased with age (difference in BMI z score comparing low with high education, at age 2-3 years = 0.03 (95% confidence interval (CI): 0.00, 0.05), at 4-7 years = 0.16 (95% CI: 0.14, 0.17), and at 8-13 years = 0.24 (95% CI: 0.22, 0.26)). Gestational diabetes was positively associated with BMI from age 8 years (BMI z score difference = 0.18, 95% CI: 0.12, 0.25) but not at younger ages; however, associations attenuated towards the null when restricted to cohorts that measured gestational diabetes via universal screening. Exposure to green vegetation was weakly associated with higher BMI up to age 1 year but not at older ages. Opportunities of cross-cohort federated analyses are discussed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Single-nucleotide polymorphisms (SNPs) in fatty acid desaturase (FADS) genes may modify dietary fatty acid requirements and influence cardiometabolic health (CMH)., Objectives: We evaluated the role of selected variants in maternal and offspring FADS genes on offspring CMH at the age of 11 y and assessed interactions of genotype with diet quality and prenatal docosahexaenoic acid (DHA) supplementation., Methods: We used data from offspring (n = 203) born to females who participated in a randomized controlled trial of DHA supplementation (400 mg/d) from midgestation to delivery. We generated a metabolic syndrome (MetS) score from body mass index, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and fasting glucose and identified 6 distinct haplotypes from 5 offspring FADS SNPs. Dietary n-6 (ω-6):n-3 fatty acid ratios were derived from 24-h recall data (n = 141). We used generalized linear models to test associations of offspring diet and FADS haplotypes with MetS score and interactions of maternal and offspring FADS SNP rs174602 with prenatal treatment group and dietary n-6:n-3 ratio on MetS score., Results: Associations between FADS haplotypes and MetS score were null. Offspring SNP rs174602 did not modify the association of prenatal DHA supplementation with MetS score. Among children with TT or TC genotype for SNP rs174602 (n = 88), those in the highest n-6:n-3 ratio tertile (>8.61) had higher MetS score relative to the lowest tertile [<6.67) (Δ= 0.36; 95% confidence interval (CI): 0.03, 0.69]. Among children with CC genotype (n = 53), those in the highest n-6:n-3 ratio tertile had a lower MetS score relative to the lowest tertile (Δ= -0.23; 95% CI: -0.61, 0.16)., Conclusions: There was evidence of an interaction of offspring FADS SNP rs174602 with current dietary polyunsaturated fatty acid intake, but not with prenatal DHA supplementation, on MetS score. Further studies may help to determine the utility of targeted supplementation strategies and dietary recommendations based on genetic profile., (Copyright © 2024. Published by Elsevier Inc.)

Background: Meeting increased regulatory requirements for clinical evaluation of medical devices marketed in Europe in accordance with the Medical Device Regulation (EU 2017/745) is challenging, particularly for high-risk devices used in children., Methods: Within the CORE-MD project, we performed a scoping review on evidence from clinical trials investigating high-risk paediatric medical devices used in paediatric cardiology, diabetology, orthopaedics and surgery, in patients aged 0-21 years. We searched Medline and Embase from 1st January 2017 to 9th November 2022., Results: From 1692 records screened, 99 trials were included. Most were multicentre studies performed in North America and Europe that mainly had evaluated medical devices from the specialty of diabetology. Most had enrolled adolescents and 39% of trials included both children and adults. Randomized controlled trials accounted for 38% of the sample. Other frequently used designs were before-after studies (21%) and crossover trials (20%). Included trials were mainly small, with a sample size <100 participants in 64% of the studies. Most frequently assessed outcomes were efficacy and effectiveness as well as safety., Conclusion: Within the assessed sample, clinical trials on high-risk medical devices in children were of various designs, often lacked a concurrent control group, and recruited few infants and young children., Impact: In the assessed sample, clinical trials on high-risk medical devices in children were mainly small, with variable study designs (often without concurrent control), and they mostly enrolled adolescents. We provide a systematic summary of methodologies applied in clinical trials of medical devices in the paediatric population, reflecting obstacles in this research area that make it challenging to conduct adequately powered randomized controlled trials. In view of changing European regulations and related concerns about shortages of high-risk medical devices for children, our findings may assist competent authorities in setting realistic requirements for the evidence level to support device conformity certification., (© 2023. The Author(s).)

This clinical practice guideline on the supply of the omega-3 docosahexaenoic acid and eicosapentaenoic acid in pregnant women for risk reduction of preterm birth and early preterm birth was developed with support from several medical-scientific organizations, and is based on a review of the available strong evidence from randomized clinical trials and a formal consensus process. We concluded the following. Women of childbearing age should obtain a supply of at least 250 mg/d of docosahexaenoic+eicosapentaenoic acid from diet or supplements, and in pregnancy an additional intake of ≥100 to 200 mg/d of docosahexaenoic acid. Pregnant women with a low docosahexaenoic acid intake and/or low docosahexaenoic acid blood levels have an increased risk of preterm birth and early preterm birth. Thus, they should receive a supply of approximately 600 to 1000 mg/d of docosahexaenoic+eicosapentaenoic acid, or docosahexaenoic acid alone, given that this dosage showed significant reduction of preterm birth and early preterm birth in randomized controlled trials. This additional supply should preferably begin in the second trimester of pregnancy (not later than approximately 20 weeks' gestation) and continue until approximately 37 weeks' gestation or until childbirth if before 37 weeks' gestation. Identification of women with inadequate omega-3 supply is achievable by a set of standardized questions on intake. Docosahexaenoic acid measurement from blood is another option to identify women with low status, but further standardization of laboratory methods and appropriate cutoff values is needed. Information on how to achieve an appropriate intake of docosahexaenoic acid or docosahexaenoic+eicosapentaenoic acid for women of childbearing age and pregnant women should be provided to women and their partners., (Copyright © 2023. Published by Elsevier Inc.)

Our aim was to assess the nutritional safety and suitability of an infant formula manufactured from extensively hydrolyzed protein in comparison to infant formula manufactured from intact protein (both with low and standard protein content). We performed a combined analysis of raw data from two randomized infant feeding studies. An analysis of covariance (ANCOVA) model was used to determine the non-inferiority of daily weight gain (primary outcome; margin -3 g/day), with the intervention group as a fixed factor and geographic region, sex, and baseline weight as covariates (main model). The data of 346 infants exposed to the formula were included in the analysis. The sample size of the per-protocol analysis with 184 infants was too small to achieve sufficient statistical power. The lower limit of the 97.5% confidence interval (-0.807) of the mean group difference in daily weight gain (i.e., 2.22 g/day) was above the -3 g/day margin (full analysis set). Further anthropometric parameters did not differ between the infant formula groups throughout the study. Growth was comparable to breastfed infants. We conclude that the infant formula manufactured from extensively hydrolyzed protein meets infant requirements for adequate growth and does not raise any safety concerns., Competing Interests: A.K. and B.K. declare no conflicts of interest. M.F. is employed by HiPP GmbH & Co. Vertrieb KG, which provided the product and financially sponsored the two studies. M.F. was involved in the design of the combined analysis, the interpretation of the data, and the writing of the manuscript.

Introduction: Hypercholesterolemia is a risk factor for premature arteriosclerosis. Inflammation and oxidative stress are thought to contribute to endothelial dysfunction preceding vasculopathy. We investigated the association between inflammation, glycocalyx biomarkers, endothelial function, and vascular parameters in children with hypercholesterolemia., Methods: In 22 patients (LDL-cholesterol &gt;130 mg/dL; median age [IQR]: 13 [2.3] years) and 22 controls (13 [2.5] years), tumor necrosis factor-alpha (TNF-α), oxidized cholesterol (oxLDL), and glycocalyx biomarkers (Syndecan-1, Hyaluronan) were measured using immunoassays. Endothelial function was assessed by peripheral arterial tonometry, sublingual glycocalyx and microcirculation by videomicroscopy and carotid intima-media thickness by ultrasound., Results: OxLDL was significantly higher in patients (78.9 [38.2] vs. 50.3 [16.6] U/L, p = 0.002), whereas all other experimental parameters were comparable between groups. Multivariate analysis revealed a significant association of Syndecan-1 with TNF-α (β = 0.75, p &lt; 0.001) and with hypercholesterolemia (β = 0.31, p = 0.030). The interaction term combining TNF-α and hypercholesterolemia showed a significant effect (p = 0.034). Sex was an independent predictor of endothelial function., Conclusion: The combined effect of hypercholesterolemia and inflammation on glycocalyx perturbation and the impact of sex in the premature development of arteriosclerosis deserve further evaluation. Therapeutic approaches tackling low-grade systemic inflammation may offer potential to prevent or delay progression of cardiovascular disease and cardiovascular complications., (© 2024 S. Karger AG, Basel.)

Introduction: Dietary fat intake in pregnancy, lactation, and childhood determines child growth, neurodevelopment, and long-term health., Methods: We performed a scoping review of dietary guidelines on fat intake for pregnant and lactating women, infants, children, and adolescents. We systematically searched several databases and websites for relevant documents published in English from 2015 to 2019., Results: We included 14 documents. Of those, eight targeted pregnant and/or lactating women, mainly recommending daily intake of approx. 250 mg/d of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), while one advised supplementing 800 mg/d DHA and 100 mg/d EPA in women of low omega-3 fatty acid status. The number of guidelines for infants was low (n = 3). Recommended intakes of total fat were 30-40% and 20-35% of total energy intake (TEI) for infants and children, respectively. Intakes of saturated fatty acids (SFAs) &lt;10% of TEI and avoidance of trans-fatty acids (TFAs) were recommended across childhood. The methodology applied to develop guidelines and to grade the strength of recommendations was heterogeneous., Conclusion: Quantitative recommendations on fat intake during pregnancy focused mainly on PUFA intake, and those targeting infants were limited. Consistent recommendations were provided for total fat, SFA, and TFA intake in childhood; however, strength of recommendation was mostly not reported., (© 2023 S. Karger AG, Basel.)

Introduction: The European Union stipulates transnational recognition of professional qualifications for several sectoral professions, including medical doctors. The Union of European Medical Specialists (UEMS), in its "Charter on Training of Medical Specialists," defines the principles for high-level medical training. These principles are manifested in the framework for European Training Requirements (ETR), ensuring medical training reflects modern medical practice and current scientific findings. In 1998, the European Society for Paediatric Research developed the first ETR for Neonatology. We present the ETR Neonatology in its third iteration (ETR III), ratified by the European Academy of Paediatrics (EAP), and approved by UEMS in 2021., Methods: In generating the ETR III, existing European policy documents on training requirements, including national syllabi and the European Standards of Care for Newborn Health were considered. To ensure the ETR III meets a pan-European standard of expertise in Neonatology, input from representatives from 27 European national paediatric/neonatal societies, and a European parent organisation, was sought., Results: The ETR III summarises the requirements of contemporary training programs in Neonatology and offers a system for accrediting trainers and training centres. We describe the content of the ETR III training syllabus and means of gaining and assessing competency as a medical care provider in Neonatology., Conclusion: Graduates of courses following the ETR III Neonatology will obtain a certificate of satisfactory training completion which should be accepted by all European member states as a baseline qualification to practice as a specialist in neonatal medicine, enabling mutual recognition of status throughout Europe., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Short sleep duration has been linked to adverse behavioral and cognitive outcomes in schoolchildren, but few studies examined this relation in preschoolers. We aimed to investigate the association between parent-reported sleep duration at 3.5 years and behavioral and cognitive outcomes at 5 years in European children. We used harmonized data from five cohorts of the European Union Child Cohort Network: ALSPAC, SWS (UK); EDEN, ELFE (France); INMA (Spain). Associations were estimated through DataSHIELD using adjusted generalized linear regression models fitted separately for each cohort and pooled with random-effects meta-analysis. Behavior was measured with the Strengths and Difficulties Questionnaire. Language and non-verbal intelligence were assessed by the Wechsler Preschool and Primary Scale of Intelligence or the McCarthy Scales of Children's Abilities. Behavioral and cognitive analyses included 11,920 and 2981 children, respectively (34.0%/13.4% of the original sample). In meta-analysis, longer mean sleep duration per day at 3.5 years was associated with lower mean internalizing and externalizing behavior percentile scores at 5 years (adjusted mean difference: - 1.27, 95% CI [- 2.22, - 0.32] / - 2.39, 95% CI [- 3.04, - 1.75]). Sleep duration and language or non-verbal intelligence showed trends of inverse associations, however, with imprecise estimates (adjusted mean difference: - 0.28, 95% CI [- 0.83, 0.27] / - 0.42, 95% CI [- 0.99, 0.15]). This individual participant data meta-analysis suggests that longer sleep duration in preschool age may be important for children's later behavior and highlight the need for larger samples for robust analyses of cognitive outcomes. Findings could be influenced by confounding or reverse causality and require replication., (© 2023. The Author(s).)

Background: There is limited evidence regarding long-term effects of prenatal docosahexaenoic acid (DHA) supplementation on offspring cardiometabolic health (CMH). Inconsistent results may be attributable to variants of fatty acid desaturase (FADS) genes., Objective: We aimed to evaluate the effect of prenatal DHA supplementation on offspring CMH and investigate effect modification by maternal FADS2 single nucleotide polymorphism (SNP) rs174602., Methods: We used follow-up data from a double-blind, randomized controlled trial in Mexico in which pregnant females received 400 mg/d of algal DHA or placebo from midgestation until delivery. The study sample included 314 offspring with data at age 11 y and maternal FADS genetic data (DHA: n = 160; Placebo: n = 154). We derived a Metabolic Syndrome (MetS) score from body mass index, HDL, triglycerides, fasting glucose concentrations, and systolic blood pressure. Generalized linear models were used to evaluate the effect of the intervention on offspring MetS score and test interactions between treatment group and genotype, adjusting for maternal, offspring, and household factors., Results: Offspring MetS score did not differ significantly by treatment group. We observed evidence of effect modification by maternal SNP rs174602 (P = 0.001); offspring of maternal TT genotype who received DHA had lower MetS score relative to the placebo group (DHA (mean ± standard error of the mean (SEM)): -0.21 ± 0.11, n = 21; Placebo: 0.05 ± 0.11, n = 23; Δ= -0.26 (95% CI: -0.55, 0.04), P = 0.09); among CC maternal genotype carriers, offspring of mothers who received DHA had higher MetS score (0.18 ± 0.06, n = 62) relative to the placebo group (-0.05 ± 0.06, n = 65, Δ=0.24 (0.06, 0.41), P < 0.01)., Conclusion: The effect of prenatal DHA supplementation on offspring MetS score differed by maternal FADS SNP rs174602. These findings further support incorporating genetic analysis of FADS polymorphisms in DHA supplementation trials., Clinical Trial Details: This trial was registered at clinicaltrials.gov as NCT00646360., Competing Interests: Conflicts of interest Usha Ramakrishnan is a member of the Journal’s Editorial Board., (Copyright © 2023. Published by Elsevier Inc.)

The primary objective of the RisCoin study was to investigate the interplay of genetic, metabolic, and lifestyle factors as well as stress levels on influencing the humoral immune response after at least two COVID-19 vaccinations, primarily with mRNAs, and the risk of SARS-CoV-2 breakthrough infections during follow-up. Here, we describe the study design, procedures, and study population. RisCoin is a prospective, monocentric, longitudinal, observational cohort study. Between October and December 2021, 4515 participants with at least two COVID-19 vaccinations, primarily BNT162b2 and mRNA-1273, were enrolled at the LMU University Hospital of Munich, thereof > 4000 healthcare workers (HCW), 180 patients with inflammatory bowel disease under immunosuppression, and 119 patients with mental disorders. At enrollment, blood and saliva samples were collected to measure anti-SARS-CoV-2 antibodies, their neutralizing capacity against Omicron-BA.1, stress markers, metabolomics, and genetics. To ensure the confidential handling of sensitive data of study participants, we developed a data protection concept and a mobile application for two-way communication. The application allowed continuous data reporting, including breakthrough infections by the participants, despite irreversible anonymization. Up to 1500 participants attended follow-up visits every two to six months after enrollment. The study gathered comprehensive data and bio-samples of a large representative HCW cohort and two patient groups allowing analyses of complex interactions. Our data protection concept combined with the mobile application proves the feasibility of longitudinal assessment of anonymized participants. Our concept may serve as a blueprint for other studies handling sensitive data on HCW., (© 2023. The Author(s).)

Autism Spectrum Disorder (ASD) is a diverse neurodevelopmental condition. Gene-environmental interactions in early stages of life might alter metabolic pathways, possibly contributing to ASD pathophysiology. Metabolomics may serve as a tool to identify underlying metabolic mechanisms contributing to ASD phenotype and could help to unravel its complex etiology. In a population-based, prospective cohort study among 783 mother-child pairs, cord blood serum concentrations of amino acids, non-esterified fatty acids, phospholipids, and carnitines were obtained using liquid chromatography coupled with tandem mass spectrometry. Autistic traits were measured at the children's ages of 6 ( n = 716) and 13 ( n = 648) years using the parent-reported Social Responsiveness Scale. Lower cord blood concentrations of SM.C.39.2 and NEFA16:1/16:0 were associated with higher autistic traits among 6-year-old children, adjusted for sex and age at outcome. After more stringent adjustment for confounders, no significant associations of cord blood metabolites and autistic traits at ages 6 and 13 were detected. Differences in lipid metabolism (SM and NEFA) might be involved in ASD-related pathways and are worth further investigation.

Several high-risk medical devices for children have become unavailable in the European Union (EU), since requirements and costs for device certification increased markedly due to the EU Medical Device Regulation. The EU-funded CORE-MD project held a workshop in January 2023 with experts from various child health specialties, representatives of European paediatric associations, a regulatory authority and the European Commission Directorate General Health and Food Safety. A virtual follow-up meeting took place in March 2023. We developed recommendations for investigation of high-risk medical devices for children building on participants' expertise and results of a scoping review of clinical trials on high-risk medical devices in children. Approaches for evaluating and certifying high-risk medical devices for market introduction are proposed., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: Lifestyle behaviours related to diet and physical activity are associated with increased risk of obesity and evidence suggests that associations might be stronger when a synergetic effect is examined., Objective: To examine the cross-sectional and longitudinal associations between diet, screen time (ST) and step recommendations and risk of overweight and obesity in European preschoolers participating in the ToyBox-study., Methods: In this cluster-randomized clinical trial, 718 children (51.4% boys) from six European countries participated. Parents filled out questionnaires with information on socio-demographic status, step recommendations and ST., Results: Longitudinal results indicate that participants having a low Diet Quality Index (DQI), not meeting ST and step recommendations at T0 and T1 had higher odds of having overweight/obesity at T1 (odds ratio [OR] = 1.116; 95% confidence interval [CI] = 1.104-2.562) than those children having a high DQI and meeting ST and step recommendations at T0 and T1. Similarly, participants having a high DQI, but not meeting ST and step recommendations at T0 and T1 had increased odds of having overweight/obesity (OR = 2.515; 95% CI = 1.171-3.021)., Conclusions: The proportion of participants having a low DQI, not adhering to both step and ST recommendations was very high, and it was associated with a higher probability of having overweight and obesity., (© 2023 The Authors. Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear., Methods: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points., Results: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N)., Conclusions: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Children and adolescents are no longer a priority in the most recent European Programme of Work (EPW) 2020-2025 of the World Health Organization (WHO) Regional Office for Europe. In this position statement we provide arguments for why we think this population should be explicitly addressed in this important and influential document. We firstly emphasize the persistent health problems and inequalities in access to care for children and adolescents that are challenging to solve, and thus require a continuous focus. Secondly, we urge the WHO to prioritize children and adolescents in their EPW due to the new and emerging health problems related to global issues. Finally, we explain why permanent prioritization of children and adolescents is essential for the future of children and of society., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Jansen, Brenner, Illy, Dembiński, del Torso, Grossman, Valiulis, De Guchtenaere, Mazur, Da Dalt, Størdal, Koletzko and Hadjipanayis.)

Background: The EU LifeCycle Project was launched in 2017 to combine, harmonize, and analyze data from more than 250,000 participants across Europe and Australia, involving cohorts participating in the EU-funded LifeCycle Project. The purpose of this cohort description is to provide a detailed overview of the major measures within mental health domains that are available in 17 European and Australian cohorts participating in the LifeCycle Project., Methods: Data on cognitive, behavioral, and psychological development has been collected on participants from birth until adulthood through questionnaire and medical data. We developed an inventory of the available data by mapping individual instruments, domain types, and age groups, providing the basis for statistical harmonization across mental health measures., Results: The mental health data in LifeCycle contain longitudinal and cross-sectional data from birth throughout the life course, covering domains across a wide range of behavioral and psychopathology indicators and outcomes, including executive function, depression, ADHD, and cognition. These data span a unique combination of qualitative data collected through behavioral/cognitive/mental health questionnaires and examination, as well as data from biological samples and indices in the form of imaging (MRI, fetal ultrasound) and DNA methylation data. Harmonized variables on a subset of mental health domains have been developed, providing statistical equivalence of measures required for longitudinal meta-analyses across instruments and cohorts., Conclusion: Mental health data harmonized through the LifeCycle project can be used to study life-course trajectories and exposure-outcome models that examine early life risk factors for mental illness and develop predictive markers for later-life disease.

Introduction: Atopic dermatitis (AD) is a chronic, inflammatory skin condition significantly affecting quality of life. A small randomised trial showed an approximately one-third lower incidence of AD in goat milk formula-fed compared with cow milk formula-fed infants. However, due to limited statistical power, AD incidence difference was not found to be significant. This study aims to explore a potential risk reduction of AD by feeding a formula based on whole goat milk (as a source of protein and fat) compared with a formula based on cow milk proteins and vegetable oils., Methods and Analysis: This two-arm (1:1 allocation), parallel, randomised, double-blind, controlled nutritional trial shall enrol up to 2296 healthy term-born infants until 3 months of age, if parents choose to start formula feeding. Ten study centres in Spain and Poland are participating. Randomised infants receive investigational infant and follow-on formulas either based on whole goat milk or on cow milk until the age of 12 months. The goat milk formula has a whey:casein ratio of 20:80 and about 50% of the lipids are milk fat from whole goat milk, whereas the cow milk formula, used as control, has a whey:casein ratio of 60:40 and 100% of the lipids are from vegetable oils. The energy and nutrient levels in both goat and cow milk formulas are the same. The primary endpoint is the cumulative incidence of AD until the age of 12 months diagnosed by study personnel based on the UK Working Party Diagnostic Criteria. The secondary endpoints include reported AD diagnosis, measures of AD, blood and stool markers, child growth, sleep, nutrition and quality of life. Participating children are followed until the age of 5 years., Ethics and Dissemination: Ethical approval was obtained from the ethical committees of all participating institutions., Trial Registration Number: NCT04599946., Competing Interests: Competing interests: SG is an employee of DGC (Dairy Goat Co-operative (NZ), Hamilton, New Zealand)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Human milk is the sole source of folate in exclusively breastfed infants. We investigated whether human milk folate or maternal plasma folate are associated with infants' folate status and postnatal growth in the first 4 months of life., Methods: Exclusively breastfed infants (n = 120) were recruited at age < 1 month (baseline). Blood samples were available at baseline and at the age of 4 months. Plasma and breastmilk samples were available from the mothers at 8 weeks postpartum. The concentrations of (6S)-5-methyltetrahydrofolate (5-MTHF) and different folate status markers were measured in samples of the infants and their mothers. The z-scores of weight, height, and head circumference of the infants were measured five times between baseline and 4 months., Results: Women with 5-MTHF concentrations in breastmilk <39.9 nmol/L (median) had higher plasma 5-MTHF compared to those with milk 5-MTHF concentrations >39.9 nmol/L (mean (SD) plasma 5-MTHF = 23.3 (16.5) vs. 16.6 (11.9) nmol/L; p = 0.015). At the age of 4 months, infants of women who were higher suppliers of 5-MTHF in breastmilk had higher plasma folate than those of low-supplier women (39.2 (16.1) vs. 37.4 (22.4) nmol/L; adjusted p = 0.049). The concentrations of breastmilk 5-MTHF and maternal plasma folate were not associated with infants' longitudinal anthropometric measurements between baseline and 4 months., Conclusions: Higher 5-MTHF in breastmilk was associated with higher folate status in the infants and the depletion of folate in maternal circulation. No associations were seen between maternal or breastmilk folate and infants' anthropometrics. Adaptive mechanisms might counteract the effect of low milk folate on infant development.

Background: Folate intake and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene may affect folate metabolism in infants., Objectives: We investigated the association between infant's MTHFR C677T genotype, the dietary folate source, and concentrations of folate markers in the blood., Methods: We studied 110 breastfed infants (reference) and 182 infants who were randomly assigned to receive infant formulas enriched with either 78 μg folic acid or 81 μg (6S)-5-methyltetrahydrofolate (5-MTHF) per 100 g milk powder for 12 wk. The blood samples were available at the ages of <1 mo (baseline) and 16 wk. MTHFR genotype and concentrations of folate markers and catabolites [i.e., para-aminobenzoylglutamate (pABG)] were analyzed., Results: At baseline, carriers of the TT genotype (vs. CC) had lower mean (SD) concentrations (all in nmol/L) of red blood cell (RBC) folate [1194 (507) vs. 1440 (521), P = 0.033) and plasma pABG [5.7 (4.9) vs. 12.5 (8.1), P < 0.001] but higher plasma 5-MTHF [33.9 (16.8) vs. 24.0 (12.6), P < 0.001]. Irrespective of the genotype, infant formula with 5-MTHF (vs. folic acid) caused a significant increase in RBC folate concentration [1278 (466) vs. 947 (552), P < 0.001]. In breastfed infants, plasma concentrations of 5-MTHF and pABG increased significantly by 7.7 (20.5) and 6.4 (10.5), respectively, from baseline to 16 wk. Infant formula that complies with the present EU legislation for folate intake increased RBC folate and plasma pABG concentrations at 16 wk (P < 0.001) than formula-fed infants. At 16 wk, plasma pABG concentrations remained ∼50% lower in carriers of the TT (vs. the CC) genotype among all feeding groups., Conclusions: Folate intake from infant formula according to the present EU legislation increased RBC folate and plasma pABG concentrations in infants to a greater extent than breastfeeding, particularly in carriers of the TT genotype. However, this intake did not completely abolish the between-genotype differences in pABG. Whether these differences have any clinical relevance, however, remains unclear. This trial was registered at clinicaltrials.gov as NCT02437721., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

We aimed to investigate the eating frequency (EF) in children over age, and examined the influence of country, sex, feeding mode and weight status on EF. We used the dietary data of the Childhood Obesity Project, which comprised European children from five countries. Dietary data of 3-days weighed and estimated records were available monthly from 1 to 9 and at 12-, 24-, 36-, 48-, 60-, 72- and 96-months old. Generalized additive mixed effects models were used to estimate EF trajectories with EF as outcome and applying age splines. Additionally, the models were further adjusted for country, feeding mode, sex or weight status. Data from 1244 children were analysed. EF was highest at 1 month with on average 7.3 ± 1.9 feeds per day, and fell to 5.1 ± 1.1 eating occasions at the age 96 months. Night feeding was similarly often than day feeding at 1 month but declined thereafter. Significant differences in EF were observed between countries ( p < 0.05), with the highest EF in Poland, and between infant feeding modes, with a higher EF in breastfed than non-breastfed infants ( p < 0.05). Sex and body weight were not associated with EF. Despite the importance of EF towards total energy intake, no association with weight status was found.

High protein intake has been associated with kidney hypertrophy, which is usually reversible; however, when it occurs early in life, it could lead to cell programming with a long-lasting effect. This study aimed to assess whether higher protein ingestion early in life has a persistent effect on kidney volume at 11 years of age, as well as its influence on blood pressure. This is a secondary analysis of a randomized control trial that compared the growth of infants fed with a higher-protein formula versus those fed with a lower-protein formula, with a control group of breastfed infants. Renal ultrasound and anthropometric measurements were assessed at 6 months and 11 years of age. At 11 years, urinary protein, albumin and creatinine, and blood pressure were measured in 232 children. Feeding with a higher-protein formula was associated with a larger kidney volume (β = 8.71, 95%CI 0.09-17.33, p = 0.048) and higher systolic blood pressure (β = 3.43, 95%CI 0.78-6.08, p = 0.011) at 11 years of age. Microalbuminuria was detected in 7% of the patients, with no differences among groups ( p = 0.56). The effect of increased protein ingestion early in life may condition kidney volume and blood pressure in later childhood.

Purpose: We aimed to characterize the distribution of energy and macronutrient intakes across eating occasions (EO) in European children from preschool to school age., Methods: Data from 3-day weighed food records were collected from children at ages 3, 4, 5, 6 and 8 years from Belgium, Germany, Italy, Poland and Spain. Food intakes were assigned to EO based on country-specific daytimes for breakfast, lunch, supper and snacks (morning, afternoon). The average energy and nutrient intakes were expressed as percentage of total energy intake (%E). Nutrients were additionally expressed as percentage per EO (%E EO ). Foods were assigned to food groups; variation in intake was calculated via coefficient of variation (CV). We analyzed age trends in diurnal intake using mixed-effects beta regression., Results: The 740 healthy children included in the analysis consumed the largest proportion of daily energy at lunch (31%E ± 8, M ± SD) and supper (26%E ± 8), followed by breakfast (19%E ± 7) and snacks [afternoon (16%E ± 8); morning (8%E ± 7)], with the most variable intake at morning snack (CV = 0.9). The nutrient composition at lunch and supper was highest for fat (36 ± 9%E Lunch ; 39 ± 11%E Supper ) and protein (18 ± 5%E Lunch ; 18 ± 6%E Supper ) and at breakfast and snacks for carbohydrates (54 ± 12%E Breakfast ; 62 ± 12%E Snacks ). High-sugar content foods were consumed in relatively large proportions at breakfast and snacks. Food intakes varied significantly with age, with lower snack intakes at later ages (p < 0.001)., Conclusion: Possibly unhealthy EOs with high-fat intakes and high-sugar-content foods were observed. Changes in nutrient composition of EOs may be beneficial for health., Trial Registry: ClinicalTrials.gov: NCT00338689; 19/June/2006., (© 2022. The Author(s).)

Background: Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, we aimed to examine the association between sarcopenia and the plasma metabolic profile of sarcopenic patients, measured using a targeted HPLC-MS/MS platform., Methods: Plasma samples from 22 (17 men) hip fracture patients undergoing surgery (8 sarcopenic, age 81.4+6.3, and 14 non-sarcopenic, age 78.4±8.1) were analyzed. T test, fold change, orthogonal partial least squares discriminant analysis, and sparse partial least squares discriminant analysis were used for mining significant features. Metabolite set enrichment analysis and mediation analysis by PLSSEM were thereafter performed., Results: Using a univariate analysis for sarcopenia z score, the amino acid citrulline was the only metabolite with a significant group difference after FDR correction. Positive trends were observed between the sarcopenia z score and very long-chain fatty acids as well as dicarboxylic acid carnitines. Multivariate analysis showed citrulline, non-esterified fatty acid 26:2, and decanedioyl carnitine as the top three metabolites according to the variable importance in projection using oPLS-DA and loadings weight by sPLS-DA. Metabolite set enrichment analysis showed carnitine palmitoyltransferase deficiency (II) as the highest condition related to the metabolome., Conclusions: We observed a difference in the plasma metabolic profile in association with different measures of sarcopenia, which identifies very long-chain fatty acids, Carn.DC and citrulline as key variables associated with the disease severity. These findings point to a potential link between sarcopenia and mitochondrial dysfunction and portraits a number of possible biochemical pathways which might be involved in the disease pathogenesis., (© 2023. The Author(s).)

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